The vacuolar system is a collection of membrane bound compartments in eukaryotic cells that function in the processes of endocytosis and exocytosis. They include the endoplasmic reticulum, the Golgi complex, phagosomes, lysosomes, endosomes, and secretory vesicles. Endocytosis is the process in cells of internalizing nutrients, solutes or small particles (pinocytosis) or large particles such as internalized receptors, viruses, bacteria, or bacterial toxins (phagocytosis). Exocytosis is the process of transporting molecules to the cell surface. It facilitates placement or localization of membrane-bound receptors or other membrane proteins and secretion of molecules such as hormones, neurotransmitters, digestive enzymes, and wastes.
The Golgi apparatus receives newly synthesized proteins and lipids from the endoplasmic reticulum and distributes them to the plasma membrane, lysosomes, and secretory vesicles. Lysosomes are the principal site of intracellular degradation of macromolecules. They contain some 40 types of hydrolytic enzymes including proteases, nucleases, glycosidases, lipases, phospholipases, phosphatases, and sulfatases. Endosomes function as the initial recipients of endocytosed materials before they are delivered to lysosomes.
A common property of all of these organelles is an acidic pH environment ranging from approximately pH 4.5-5.0. This acidity is maintained by the presence of various proton ATPases that use the energy of ATP hydrolysis to generate an electrochemical proton gradient across a membrane (Mellman, I. et al. (1986) Ann. Rev. Biochem. 55:663-700). The low pH has several functions in the vacuolar system. In lysosomes the low pH provides favorable conditions for enzymatic hydrolysis by acid hydrolases. In receptor-mediated endocytosis the lowering in pH between extracellular environment and the endosome induces conformational changes that permit dissociation of the receptor-ligand complex prior to returning the receptor to the cell membrane. Acid-induced conformational changes in viral proteins and bacterial toxins permit their penetration into host cells.
Recently small acidic proteins have been identified which have isoelectric points (pI) approximating that of the interior of vacuolar organelles (pI=4.5-5.0) (NCBI, GI 1276649 and GI 1915967). The function(s) of these proteins are as yet unknown, but based on their acidic nature, they may have a role in activity of one or more of the organelles of the vacuolar system.
Defects or alterations in the vacuolar system may be involved in a variety of diseases and disorders. Lysosomal storage diseases are caused by genetic defects affecting one or more of the lysosomal hydrolases and result in accumulation of undigested substrates with severe pathological consequences. Failure of hormones and neurotransmitters to be secreted by the exocytic pathway can result in various hormonal and neurological disorders. Additionally, inhibition of the endocytic pathway by alteration of vacuolar pH may be employed to prevent the spread of many viruses and bacterial toxins that depend on vacuolar acidity for host cell invasion (Mellman, et al., supra).
The discovery of a new disease associated acidic protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer, immune disorders, and neurological disorders.